Obesity is an independent risk factor for atherosclerotic vascular disease. Several recent studies suggest that elevated plasma leptin is associated with cardiovascular risk. Leptin, a peptide secreted by adipocytes, binds to specific teptin receptors in the hypothalamus and has downstream effects on feeding behavior and energy balance. Abdominal obesity and leptin levels correlate with noninvasive measurements of atherosclerosis and with acute coronary events, even after correction for insulin sensitivity, glucose and lipid abnormalities. An unexplored issue is whether elevated levels of leptin can have direct effects on the cells of the vessel wall to alter the progression of vascular disease. Leptin receptors have been detected on the cell types present in vascular lesions such as endothelial cells, macrophages, lymphocytes and smooth muscle cells. In cell culture models, leptin has been shown to affect processes relevant to atherosclerosis such as endothelial proliferation, angiogenesis, macrophage activation, and macrophage inflammatory cytokine secretion. The experiments proposed in this application will evaluate whether obesity promotes vascular disease through direct effects of leptin on the vessel wall. Preliminary data suggests that leptin affects smooth muscle ceil proliferation/migration in an in vivo model of vascular injury. In this application, experiments are proposed to evaluate the direct effect of leptin on atherosclerosis and on arterial injury by selectively knocking out leptin receptors in smooth muscle cells, macrophages and endothelial cells. Macrophage, smooth muscle cell, and endothelial cell cre recombinase expressing transgenic mice will be individually crossed to floxed leptin receptor mutant mice to selectively knock out leptin receptors in a tissue specific manner. Compound mutant mice will be then crossed with LDL receptor knockout mice to create models of obesity, insulin resistance, hyperlipidemia, and atherosclerosis in which leptin receptors are lacking in a single cell type. The response to endoluminal arterial injury will also be evaluated in cell specific knockouts of the leptin receptor and in diet induced obese, agouti and ob/ob mice. The role of leptin in smooth muscle migration and proliferation will be examined using primary aortic smooth muscle cells. The proposed experiments will provide insight into the biologic mechanisms by which obesity promotes atherosclerotic vascular disease.